The development of vaccines capable of eliciting a immune responses protective against HIV infection has been hampered by the lack of a small animal model susceptible to HIV infection. Despite the identification of CD4 as the primary cellular receptor for HIV, expression of human CD4 transgene alone did not render mice susceptible to HIV infection. The mechanistic basis for this restriction has recently been clarified by the demonstration that, in addition to CD4, HIV must interaction with another membrane of the chemokine receptor superfamily, such as CCR5, to start the process of membrane fusion and viral penetration. We have initiated studies examining the susceptibility of mice to HIV infection using mice that we developed that are transgenic for human CD4 and CCR5. Therefore, we propose to expand on these studies and to develop mice transgenic for human CD4 and other human chemokine receptors as a model for studying the role of the immune system in controlling HIV infection and for evaluating HIV vaccines. Because HIV infection of mouse cells is also compromised by defective function of HIV regulatory genes such as tat and rev, the usefulness of these transgenic mice for studying HIV infection will require the generation of isolates of HIV that are better suited fir growth in mouse cells. One approach we will use to generate these isolates will be to adapt HIV for growth in mouse cells by serial in vivo or in vitro passage. Another passage that we will take will be to construct HIV clones with alternative regulatory sequences designed to circumvent post- penetration blocks that impede HIV replication in murine cells. After generating the transgenic mice and permissive HIV isolates, we will use a genetic approach to delineate the immune responses necessary and sufficient for protection against HIV infection. The transgenic mice will be bred into mouse lines homozygous for targeted disruptions of various critical immune response genes such as Class I MHC, Class II MHC, perforin and mu-M and then infected with HIV. This will permit us to develop a genetic approach for studying the mechanisms of immune protection and pathogenesis of HIV infection.